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Method of improving ischemic muscle function by administering placental growth factor

a technology of placental growth factor and ischemic muscle, which is applied in the field of prevention and treatment of stroke and ischemic diseases, can solve the problems of reducing the function of ischemic muscle, and reducing the risk of stroke, so as to improve the function of ischemic tissue, improve the function of ischemic muscle, and increase the expression of veg

Inactive Publication Date: 2006-09-12
D COLLEN RES FOUND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]The present invention is based on a first unexpected finding that PlGF increases VEGF expression in places where VEGF is already up-regulated, due to ischemic disease conditions, i.e. in places where VEGF is needed. The present invention is also based on a second unexpected finding that PlGF simultaneously stimulates both smooth muscle cells and endothelial cells, whereas VEGF preferentially stimulates endothelial cells. Other observations of the present inventors are that PlGF significantly increases capillary vessel density in muscles, that it is much more efficient than VEGF in stimulating collateral arteriolar growth (for instance in ischemic myocardium or in an ischemic limb). This results in an improved function of the ischemic tissue, more particularly, strongly increased limb motoric function (as could be measured in an endurance swim test). This is corroborated by limb perfusion data showing that, contrary to laser Doppler measurements, perfusion measured by microspheres is quite different in ischemic limbs treated with VEGF and PlGF respectively. PlGF efficiency is thus associated with improved perfusion as a result of constructive angiogenesis, arteriogenesis and collateral vessel growth. These qualities are of particular interest for the restoration of ischemic tissue.
[0016]The present invention is further based on the finding that administration of PlGF and VEGF has a synergistic effect in the treatment of in an animal ischemic myocardium and in suppressing infarct expansion of the penumbra.

Problems solved by technology

Ischemia of the myocardium, as a result of reduced perfusion due to chronic narrowing of blood vessels, may lead to fatal heart failure and constitutes a major health threat.
In the absence of reflow or sufficient perfusion, the cerebral or myocardial ischemic regions undergo progressive metabolic deterioration, culminating in infarction, whereas restoration of perfusion in the penumbra of the brain infarct or in the jeopardized but salvageable region of the myocardium may ameliorate the tissue damage.
Thus, despite a slight increase in collateral growth and hind limb perfusion, the overall functional reserve after VEGF treatment was impaired, presumably because of unfavorable hemodynamic effects.
In other words, it is known that despite vessel formation by means of VEGF, the functionality of the vessels formed is very low.
Despite promising initial clinical trials, a large double-blind placebo-controlled trial testing the efficacy of intracoronary and intravenous VEGF for therapeutic angiogenesis in patients with chronic myocardial ischemia not amenable to standard revascularization techniques, indicated that even high dose treatment with VEGF did not lead to a significant improvement in ETT time (Henry et al.

Method used

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  • Method of improving ischemic muscle function by administering placental growth factor
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Examples

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Effect test

example 1

Protection Against Cerebral Ischemic Infarct Expansion by Chronic Administration of PlGF

[0085]Infarcted mice were treated with saline (for control), PlGF (715 ng / day) or VEGF days (425 ng / day) or a combination of both. The data of these experiments, presented in Table 1 below, are the mean+-standard error of mean (SEM) values of the infarct size expressed in mmand used as a means for measuring cerebral infarction, including the number of observations between brackets and wherein an asterisk means p=0.001 vs. control. The significance of differences was determined by unpaired t-test. Intracerebral bleeding was not observed in any of the mice. These data indicate that PlGF is as effective as PlGF in suppressing infarct expansion of the penumbra. These data also indicate that there is a synergistic effect of VEGF and PlGF in suppressing infarct expansion of the penumbra

[0086]

TABLE 1Treatment groupInfarct sizeControl 12 ± 1.7 (7)PIGF8.0 ± 2.9 (4)VEGF7.6 ± 2.5 (3)PIGF + VEGF4.6 ± 1.3 (8)...

example 2

Enhanced Revascularization of Acute Myocardial Infarcts by Chronic Administration of PlGF

[0087]The therapeutic effect of PlGF and VEGF was compared in a murine model for acute myocardial infarction by delivering the growth factors continuously over 7 days. Treatment of infarcted mice with PlGF (715 ng / day or 3.5 μg / day) was more effective than VEGF (450 ng / day) in improving myocardial angiogenesis and arteriogenesis, as shown in Tables 2 and 3 Moreover, a synergistic effect of PlGF and VEGF can be observed, especially in the formation of medium and large vessels. Table 2 provides the number of vessels (mean±SEM values), identified by thrombomodulin staining of endothelial cells as a measure of angiogenesis, throughout the infarct in groups of 8 to 10 mice each. An asterisk means p<0.05 vs. control. Table 3 provides the number of vessels (mean±SEM values), identified by smooth muscle alpha-actin staining of endothelial cells as a measure of arteriogenesis, throughout the infarct in g...

example 3

PlGF Delivery Did Not Cause Side Effects

[0095]At the dose of 1.5 μg, administered daily for 7 days PlGF did not cause oedema or ectopic angiogenesis in the mouse model for acute myocardial infarction, while local signs of oedema were clearly present around the mini-pumps delivering VEGF. PlGF plasma levels up to about 50 ng / ml (achieved by the delivery of 7 μg hPlGF-2 per day for 7 days) were well tolerated without any sign of distress, while VEGF plasma levels above 10 ng / ml caused severe life threatening signs of oedema and circulatory shock. On the other hand, unlike VEGF, PlGF only minimally affected the blood pressure. Mean arterial blood pressure (measured using high fidelity pressure micromanometers, Miller Instruments, Houston, Tex.) was 93±5 mm Hg under baseline conditions (control mice). Intravenous bolus injection of 3 μg VEGF caused significant hypotension (68±3 mm Hg; p<0.05), while 5 to 10 μg hPlGF-2 did not significantly reduce arterial blood pressure (91±11 mm Hg). T...

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Abstract

The present invention relates to prevention and treatment of strokes and ischemic diseases and to post-ischemic therapeutic treatment. The invention furthermore relates to the use of a growth factor for treating, more particularly restoring the function of ischemic tissue, in particular muscles such as myocardium and skeletal muscles.

Description

RELATED APPLICATIONS[0001]This application is the non-provisional filing of provisional application No. 60 / 386,116, filed, Jun. 4, 2002. This application is also a continuation-in-part of U.S. patent application Ser. No. 10 / 182,359, filed Sep. 23, 2002 (now U.S. Pat. No. 6,930,089), which is the national filing of international application number PCT / EP01 / 01208 with an international filing date of Feb. 5, 2001.FIELD OF THE INVENTION[0002]The present invention relates to prevention and treatment of strokes and ischemic diseases and to post-ischemic therapeutic treatment. The invention furthermore relates to the use of a growth factor for treating, more particularly restoring the function of ischemic tissue, in particular muscles such as myocardium and skeletal muscles. The present invention also relates to a method of curing a reduced (e.g. muscular) performance in a mammal, in particular a human being, after an ischemic event. Advantageously the present invention is concerned with t...

Claims

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Application Information

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IPC IPC(8): A61K38/18C07K14/475
CPCA61K38/1891A61K38/1866
Inventor CARMELIET, PETERCOLLEN, DESIRE
Owner D COLLEN RES FOUND
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